This invention was made with Government support under Contract No. DE-AC03-76SF00098 between the U.S. Department of Energy and the University of California for the operation of Lawrence Berkeley Laboratory. The Government has certain rights in this invention.
1. Field of the Invention
The present invention relates to certain substituted 6-nitroquipazines, to methods for their preparation, to radiolabeled derivatives thereof, and methods of use.
2. Related Art
In the treatment of mental disease, particularly depression, certain types of drugs have been found to be efficacious over the years. In particular, the so-called "tricyclic" compounds such as imipramine, amitriptyline, nortriptyline, and others have been used to counter the effects of depression. The mode of action of the tricyclic drugs appear to be that of an inhibitor of monoamine uptake, i.e., a 5-HT (5-hydroxytryptamine) uptake inhibitor.
The tricyclics and some new anti-depressant drugs not only inhibit monoamine uptake, but also bind directly with some neurotransmitter receptors. Antagonism of the receptor function is believed to contribute to certain side effects of anti-depressant drugs, such as dry mouth, dizziness, blurred vision, constipation, urinary retention, tachycardia, and memory disfunction. Antagonism of central H.sub.1 histamine receptors may contribute to sedation or drowsiness and also to the weight gain associated with certain anti-depressants.
Because of the side effects of tricyclics, pharmaceutical companies are constantly on the lookout for more specific 5-HT uptake inhibitors which do not have the same side effects as the tricyclic compounds.
A series of more or less selective 5-HT uptake inhibitors has appeared in the literature in recent years. One of such compounds is fluoxetine, whose chemical name is (.+-.)-N--Methyl-3-Phenyl-3-[(.alpha..alpha..alpha.-trifluoro-p-tolyl)oxy] propylamine. This compound, in therapeutic form, is known as Prozac.
Fluoxetine, because of its 5-HT uptake inhibitor specificity, does not have the common side effects associated with tricyclic amines.
Because of its selective affinity for the serotonin-uptake carrier, fluoxetine has been used as a radioligand to label the carrier.
The inhibition of serotonin uptake by fluoxetine is believed to cause an increase in concentration of serotonin in the synaptic cleft, since neuronal reuptake is the physiological means of removing serotonin from that cleft.
When compared with certain tricyclic amine drugs, fluoxetine has equal anti-depressant efficacy with fewer total side effects and dropouts among fluoxetine-treated patients. Fluoxetine performs as well as the tricyclic anti-depressants in relieving the symptoms of depression and is associated with a lower dropout rate due to adverse effects.
Another compound which has been found to be effective in binding of serotonin uptake sites in a sample is 6-nitroquipazine. This compound is described in European patent application number 90125092.8, filed Dec. 21, 1990. (European patent application publication number 0435192A2.) In this patent application it is disclosed that the measurement of serotonin uptake sites in a sample can be improved by using tritium-labeled 6-nitro-2-N-piperazinylquinoline or an acid addition salt thereof as the radioligand. As stated in that patent application, the termination of the effects of serotonin in synaptic function occurs in two ways, i.e., by an uptake process and by metabolism of the transmitter. Although the details of serotonin metabolism have been clearly established, the process is believed to play a minor role in terminating the action of serotonin at the synaptic cleft. The most likely terminating process is believed to be the reuptake of serotonin by the pre-synaptic terminal. Thus, serotonin uptake sites, which exist in the pre-synaptic nerve terminal, play an important role in regulating the serotonin content in the synaptic cleft.
It has been reported that there is a reduced density of serotonin uptake sites in the brain tissue of depressed patients and Alzheimer's disease. Therefore the study of serotonin uptake sites in the brain's of people with these diseases is useful for the diagnosis and therapy of these diseases.
One means of making these measurements is by means of radio receptor assay. Radio receptor assay is a method for measuring the radioactivity of a radioligand bound to sample after incubating the radioligand and sample.
Efforts are constantly being made, however, to discover new compounds which are more efficacious in binding to serotonin uptake sites, and thereby inhibiting 5-HT uptake in the synaptic cleft.